Method for preparing a two-phase water-absorbent bioadhesive composition

ABSTRACT

A method is provided for preparing an adhesive composition that contains both a hydrophobic phase and a hydrophilic phase, wherein the hydrophobic phase is composed of a crosslinked hydrophobic polymer composition and the hydrophilic phase is a water-absorbent blend of a hydrophilic polymer and a complementary oligomer capable of crosslinking the hydrophilic polymer through hydrogen bonding, ionic bonding, and/or covalent bonding. The composition is useful as a bioadhesive, for affixing drug delivery systems, wound dressings, bandages, cushions, or the like to a body surface such as skin or mucosal tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. patent application Ser. No. 10/137,196,filed May 1, 2002, now U.S. Pat. No. 6,803,420, which claims priorityunder 35 U.S.C. § 119(e)(1) to provisional U.S. Patent Application Ser.No. 60/288,024, filed May 1, 2001 and application Ser. No. 10/137,196,filed May 1, 2002, now U.S. Pat. No. 6,803,420, issued on even dateherewith.

TECHNICAL FIELD

This invention relates generally to adhesive compositions, and moreparticularly relates to a novel adhesive composition composed of ahydrophobic phase and a hydrophilic phase. The composition is useful asa bioadhesive in a variety of contexts involving application of a drugdelivery system, wound dressing, cushion, or the like to an individual'sskin or other body surface.

BACKGROUND

Pressure-sensitive adhesives (PSAs) for application to the skin or otherbody surface are well known and have been used for many years in avariety of consumer and medical applications. Pressure-sensitiveadhesives are characterized as being normally tacky and exhibitinginstant tack when applied to a substrate. Many polymers have been usedto manufacture pressure-sensitive adhesives as, for example, acrylic andmethacrylic ester homo- or copolymers, butyl rubber-based systems,silicones, urethanes, vinyl esters and amides, olefin copolymermaterials, natural or synthetic rubbers, and the like. All the PSAs areelastomers, i.e. they exhibit viscoelastic properties typical ofrubbers.

Existing examples of pressure-sensitive adhesives used for affixing adrug delivery system, cushion, or the like to the skin includepolysiloxanes (e.g., polydimethyl siloxanes, polydiphenyl siloxanes, andsiloxane blends), polyisobutylenes, polyacrylates, acrylic acid-acrylatecopolymers (e.g., copolymers of acrylic acid copolymers with2-ethylhexyl acrylate or isooctyl acrylate), and tacky rubbers such aspolyisobutene, polybutadiene, polystyrene-isoprene copolymers,polystyrene-butadiene copolymers, and neoprene (polychloroprene). All ofthese PSAs are hydrophobic polymers and their common disadvantage is aloss in adhesion toward hydrated substrates.

“Bioadhesion” is defined as a pressure-sensitive adhesion with respectto highly hydrated biological tissues such as mucosal tissue. Incontrast to conventional pressure sensitive adhesives such as rubber,polysiloxanes, and acrylates that adhere mainly to dry substrates,bioadhesives (BAs) exhibit good tack when adhered to hydrated biologicalsubstrates. To be bioadhesive, water should provide a plasticizingeffect on a polymer, i.e., the polymer should be hydrophilic. Forexample, the range of typical BAs includes slightly cross-linkedpolyacrylic and polymethacrylic acids (EP 0 371 421) as well as blendsof hydrophilic cellulose derivatives (40-95%) with polyethylene glycol(PEG) (U.S. Pat. No. 4,713,243).

Bioadhesives become tacky as the crosslinked polymer swells insignificant quantities of water. The cohesive strength of highly swollenhydrophilic polymers is generally low and the BAs thus differ from thePSAs in this regard.

Attempts to combine the properties of PSAs and BAs have been describedby Biegajski et al. in U.S. Pat. No. 5,700,478, where a water-solublepressure-sensitive mucoadhesive was obtained by blending 95-40%polyvinylpyrrolidone (PVP) with 0-50% hydroxypropyl cellulose (HPC) and11-60% glycerol. Other examples of hydrophilic polymer blends couplingthe properties of PSAs and BAs involve polyacrylic acid-polyvinylalcohol (PAA-PVA) interpolymeric complexes formed by hydrogen bondingbetween the monomer units of the complementary polymer chains andplasticized with PEG-200, glycerol or polypropylene glycol (PPG),molecular weight 425 g/mol (German Patent Application No. DE 42 19 368).

The ideal performance characteristics of an adhesive compositionintended for use on human skin and/or mucosal tissue present difficultand conflicting technical requirements. Initially, the adhesive shouldbe suitable for long-term skin contact, and permeable to and physicallyand chemically compatible with any active agent and any permeationenhancers or other vehicles or additives that are present. The idealadhesive should also be nonirritating, noncomedogenic andnonsensitizing, yet bond quickly to skin or mucosal tissue at theintended site of use with only very slight pressure. The adhesive shouldmaintain its bond for as long a period of time as necessary and beresistant to inadvertent removal, yet be easily removed without removingany skin or leaving a residue (a suitable strength of an adhesive jointwith the skin ranges from about 200 to 400 N/m under the 180 degree peeltest). Furthermore, the adhesive composition should not be sensitive toor degradable by exposure to moisture or high humidity.

With bioadhesives, hydrophilic compositions are preferred for theadhesive compositions to adhere well to moist substrates. Hydrophilicadhesives are advantageous in other respects as well, insofar as:

-   -   (1) hydrophilic adhesives can provide greater adhesion compared        with hydrophobic adhesives, because the surface energy of        hydrophilic adhesives is typically higher and closer to that of        biological substrates such as skin and mucosal membranes;    -   (2) hydrophilic adhesives are compatible with a wide variety of        drugs, excipients and additives;    -   (3) the plasticizing effect of water sorbed by hydrophilic        adhesives from hydrated skin or mucosal tissues enhances        adhesion, in contrast to hydrophobic adhesives;

(4) the enhanced solubility of drugs in hydrophilic adhesivesfacilitates control over drug release kinetics;

-   -   (5) with hydrophilic adhesives, based on hydrophilic polymers,        there is an expanded capability to control and manipulate the        adhesive-cohesive balance; and    -   (6) the adhesive properties of hydrophilic polymers are        considerably less sensitive to their molecular weight than those        of hydrophobic polymers, as a result of specific intramolecular        and intermolecular interaction within hydrophilic adhesives.

In order to increase the hydrophilicity of an adhesive composition,hydrophobic PSAs have been “hydrophilized” by incorporation of non-tackyhydrophilic polymers and fillers into a hydrophobic adhesive. Thus,polyisobutylene (PIB) PSA has been hydrophilized by incorporation ofcellulose and cellulose derivatives (U.S. Pat. No. 4,231,369), polyvinylalcohol (PVA), pectin and gelatin (U.S. Pat. Nos. 4, 367,732 and4,867,748), and SiO₂ (U.S. Pat. No. 5,643,187). Rubber adhesives havealso been modified by filling with amphiphilic surfactants, or bytreating the PSA polymer with a plasma-oxygen discharge. Acrylic PSAscan be hydrophilized by incorporation of PVP (U.S. Pat. No. 5,645,855).Hydrophilization of hydrophobic adhesives, while somewhat effective,tends to result in a partial loss of adhesion.

There is, accordingly, a need in the art for improved bioadhesivecompositions that combine the properties of hydrophobic PSAs with themany advantages of hydrophilic adhesive compositions. It would also beideal if such an adhesive composition could be adapted for a variety ofuses, e.g., in wound healing and bandages, in the fabrication oftransdermal and other drug delivery systems, in preparing medicatedadhesive formulations for topical and transdermal pharmaceuticalformulations, in pressure-relieving cushions (which may or may not bemedicated), as sealants for ostomy devices and prostheses, as conductiveadhesives for attachment of electroconductive articles such aselectrodes to the skin, and the like.

SUMMARY OF THE INVENTION

It is a primary object of the invention to provide a novel adhesivecomposition that meets all of the above-discussed needs in the art.

In one embodiment, the invention pertains to a two-phase,water-absorbent adhesive composition that comprises a blend of ahydrophobic pressure-sensitive adhesive with a water-absorbenthydrophilic composition. As such, the composition comprises ahydrophobic phase and a hydrophilic phase, wherein the hydrophobic phaseincludes a hydrophobic polymer, e.g., a crosslinked hydrophobic polymer,preferably a hydrophobic PSA, and the hydrophilic phase comprises ablend of a relatively high molecular weight hydrophilic polymer and alower molecular weight complementary oligomer that is capable ofcrosslinking the hydrophilic polymer through hydrogen bonds, andoptionally through covalent and/or ionic bonds as well. The weight ratioof the hydrophilic polymer to the complementary oligomer is selected tooptimize the adhesive strength, cohesive strength, and hydrophilicity ofthe composition. The composition may additionally include any number ofadditives, e.g., active agents, fillers, tackifiers, and the like.

In another embodiment, a drug delivery system is provided comprising anactive agent in an adhesive composition as described above, wherein thesystem has a body-contacting surface and an outer surface, with theadhesive composition present within a region of the body-contactingsurface. The body-contacting surface may be entirely comprised of theadhesive composition, or the perimeter of the body-contacting surfacemay be composed of a different skin contact adhesive. The drug deliverysystem may be designed for systemic delivery of an active agent, e.g.,via the transdermal or transmucosal routes. The system may also bedesigned for topical administration of a locally active agent.

In a related embodiment, a wound dressing is provided comprised of asubstrate for application to the wound region, wherein the substrate hasa body-contacting surface and an outer surface, with the adhesivecomposition present in a wound-contacting region of the body-contactingsurface. As with drug delivery systems, the body-contacting surface maybe entirely comprised of the adhesive composition, although it ispreferred that the composition be present in a central region on thebody-contacting surface, with the perimeter of the body-contactingsurface composed of a different skin contact adhesive. In thisembodiment, absorption of water present in the wound exudate graduallycauses the wound dressing to lose tack.

The adhesive compositions herein are also useful in a host of additionalapplications, e.g., in various types of pharmaceutical formulations,pressure-relieving cushions (which may or may not be medicated),bandages, ostomy devices, prosthesis securing means, face masks, sound,vibration or impact absorbing materials, and the like. Also, thecompositions may be rendered electrically conductive by incorporation ofan electrically conductive material, and may thus be used for attachingan electroconductive article, such as an electrode (e.g., atranscutaneous electric nerve stimulation, or “TENS” electrode, anelectrosurgical return electrode, or an EKG monitoring electrode), to anindividual's body surface.

The adhesive compositions of the invention provide a number ofsignificant advantages relative to the prior art. In particular, thepresent compositions:

-   -   (1) may be fabricated so as to display very high swelling upon        contact with water without concomitant loss of adhesion;    -   (2) can be fabricated so as to exhibit little or no cold flow        during use;    -   (3) are useful and versatile bioadhesives in a number of        contexts, including wound dressings, active agent delivery        systems for application to a body surface, pressure-relieving        cushions, and the like; and    -   (4) are readily modified during manufacture so that properties        such as adhesive strength, cohesive strength, absorption, and        swelling can be optimized.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates one embodiment of a wound dressingprepared with an adhesive composition of the invention, wherein thedressing is composed of an outwardly facing backing layer and abody-facing skin contact adhesive layer laminated thereto, wherein anadhesive composition of the invention is present as a film on aninterior region of the body-contacting surface of the skin contactadhesive layer.

FIG. 2 schematically illustrates an alternative embodiment of a wounddressing of the invention that does not include separate backing andskin contact adhesive layers, wherein a backing layer is composed of askin contact adhesive having a nontacky outwardly facing surface and aslightly tacky body facing surface, and an adhesive composition of theinvention is present as a film on an interior region of thebody-contacting, at least slightly tacky surface of the backing layer.

FIG. 3 schematically illustrates another embodiment of a wound dressingof the invention, wherein the dressing is similar in structure to thatof FIG. 2, but includes a peripheral skin contact adhesive on thebody-contacting surface. In this case, the body-contacting surface ofthe backing layer does not need to be tacky.

FIG. 4 is a bottom plan view of the embodiment of FIG. 3 taken along the4-4 lines of that figure, and illustrates the concentric regions of thebody-contacting surface, with a peripheral skin contact adhesivesurrounding an inner region of a nontacky or slightly tacky material,which in turn contains the adhesive composition in a central regionintended as the wound-contacting region.

FIG. 5 illustrates another embodiment of a wound dressing herein whereinthe three layers of a laminated composite, an outwardly facing backinglayer, an interior pressure sensitive adhesive layer, and abody-contacting layer composed of an adhesive composition of theinvention, are coextensive.

FIG. 6 illustrates an analogous embodiment wherein the interior pressuresensitive adhesive layer is omitted, and the hydrogel-containing layeris made sufficiently tacky so that the backing layer adheres directlythereto. Again, the backing layer and the body-contacting hydrogel layerare co-extensive.

FIG. 7 shows the peel strength of PIB-BR blends pressed between apolyethylene substrate.

FIG. 8 shows the effect of curing agent concentration and temperature onthe rheokinetics of PVP-PEG hydrogel thermal crosslinking, as describedin Example 2.

FIG. 9 illustrates the curing rheokinetics of PIB-BR-Regalite mixtureswith an incorporated PVP-PEG hydrogel, as described in Example 2.

FIG. 10 shows the effect on the adhesion of PIB blends with PVP-PEG andHPC, as evaluated in Example 3.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions and Nomenclature:

Before describing the present invention in detail, it is to beunderstood that unless otherwise indicated this invention is not limitedto specific compositions, components or manufacturing processes, as suchmay vary. It is also to be understood that the terminology used hereinis for the purpose of describing particular embodiments only, and is notintended to be limiting. It must be noted that, as used in thisspecification and the appended claims, the singular forms “a,” “an,” and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a hydrophilic polymer”includes not only a single hydrophilic polymer but also a combination ormixture of two or more different hydrophilic polymers, reference to “aplasticizer” includes a combination or mixture of two or more differentplasticizers as well as a single plasticizer, and reference to “ahydrophobic pressure-sensitive adhesive” includes a mixture of two ormore such adhesives as well as a single such adhesive, and the like.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The definitions of “hydrophobic” and “hydrophilic” polymers are based onthe amount of water vapor absorbed by polymers at 100% relativehumidity. According to this classification, hydrophobic polymers absorbonly up to 1 wt. % water at 100% relative humidity (“rh”), whilemoderately hydrophilic polymers absorb 1-10% wt. % water, hydrophilicpolymers are capable of absorbing more than 10 wt. % of water, andhygroscopic polymers absorb more than 20 wt. % of water.

The term “crosslinked” herein refers to a composition containingintramolecular and/or intermolecular crosslinks, whether arising throughcovalent or noncovalent bonding. “Noncovalent” bonding includes bothhydrogen bonding and electrostatic (ionic) bonding.

The term “polymer” includes linear and branched polymer structures, andalso encompasses crosslinked polymers as well as copolymers (which mayor may not be crosslinked), thus including block copolymers, alternatingcopolymers, random copolymers, and the like. Those compounds referred toherein as “oligomers” are polymers having a molecular weight below about1000 Da, preferably below about 800 Da.

The term “hydrogel” is used in the conventional sense to refer towater-swellable polymeric matrices that can absorb a substantial amountof water to form elastic gels, wherein “matrices” are three-dimensionalnetworks of macromolecules held together by covalent or noncovalentcrosslinks. Upon placement in an aqueous environment, dry hydrogelsswell to the extent allowed by the degree of cross-linking.

The term “water-insoluble” refers to a compound or composition whosesolubility in water is less than 5 wt. %, preferably less than 3 wt. %,more preferably less than 1 wt. % (measured in water at 20° C.).

The term “active agent” is used herein to refer to a chemical materialor compound suitable for administration to a human patient and thatinduces a desired beneficial effect, e.g., exhibits a desiredpharmacological activity. The term includes, for example, agents thatare therapeutically effective, prophylactically effective, andcosmetically (and cosmeceutically) effective. Also included arederivatives and analogs of those compounds or classes of compoundsspecifically mentioned which also induce the desired beneficial effect.

By “transdermal” drug delivery is meant administration of a drug to theskin surface of an individual so that the drug passes through the skintissue and into the individual's blood stream. Unless otherwiseindicated, the term “transdermal” is intended to include “transmucosal”drug administration, i.e., administration of a drug to the mucosal(e.g., sublingual, buccal, vaginal, rectal) surface of an individual sothat the drug passes through the mucosal tissue and into theindividual's blood stream.

The term “topical administration” is used in its conventional sense tomean delivery of an active agent to a body surface such as the skin ormucosa, as in, for example, topical drug administration in theprevention or treatment of various skin disorders, the application ofcosmetics and cosmeceuticals (including moisturizers, masks, sunscreens,etc.), and the like. Topical administration, in contrast to transdermaladministration, provides a local rather than a systemic effect.

The term “body surface” is used to refer to any surface located on thehuman body or within a body orifice. Thus, a “body surface” includes, byway of example, skin, or mucosal tissue, including the interior surfaceof body cavities that have a mucosal lining. Unless otherwise indicated,the term “skin” as used herein should be interpreted as includingmucosal tissue and vice versa.

Similarly, when the term “transdermal” is used herein, as in“transdermal drug administration” and “transdermal drug deliverysystems,” it is to be understood that unless explicitly indicated to thecontrary, both “transmucosal” and “topical” administration and systemsare intended as well.

II. Adhesive Compositions:

In a first embodiment, an adhesive composition is provided that combinesthe properties of a hydrophobic PSA with the advantages of a hydrophilicadhesive composition. The composition is comprised of a hydrophobicphase and a hydrophilic phase, wherein the hydrophobic phase includes atleast one hydrophobic polymer, and the hydrophilic phase, dispersed orotherwise contained therein, is comprised of a mixture of a hydrophilicpolymer and a low molecular weight complementary oligomer capable ofhydrogen bonding thereto. The low molecular weight complementaryoligomer may also serve to crosslink the hydrophilic polymer via ionicand/or covalent bonding.

A. The Hydrophobic Phase

The hydrophobic phase is comprised of at least one hydrophobic polymer.The hydrophobic polymer is typically a hydrophobic pressure-sensitiveadhesive polymer, preferably a thermosetting polymer. Preferredhydrophobic PSA polymers are crosslinked butyl rubbers, wherein a “butylrubber,” as well known in the art, is an isoprene-isobutylene copolymertypically having an isoprene content in the range of about 0.5 to 3 wt.%, or a vulcanized or modified version thereof, e.g., a halogenated(brominated or chlorinated) butyl rubber. In a particularly preferredembodiment, the hydrophobic PSA polymer is butyl rubber crosslinked withpolyisobutylene. Other suitable hydrophobic polymers include, forexample, natural rubber adhesives, vinyl ether polymers, polysiloxanes,polyisoprene, butadiene acrylonitrile rubber, polychloroprene, atacticpolypropylene, and ethylene-propylene-diene terpolymers (also known as“EPDM” or “EPDM rubber”) (available as Trilene® 65 and Trilene® 67 fromUniroyal Chemical Co., Middlebury, Conn.). Still other suitablehydrophobic PSAs will be known to those of ordinary skill in the artand/or are described in the pertinent texts and literature. See, forexample, the Handbook of Pressure-Sensitive Adhesive Technology, 2ndEd., Satas, Ed. (New York: Von Nostrand Reinhold, 1989). Particularlypreferred hydrophobic polymers are the crosslinked butyl rubbersavailable in the Kalar® series from Elementis Specialties, Inc.(Hightstown, N.J.), with Kalar® 5200, Kalar® 5215, Kalar® 5246, andKalar® 5275 most preferred.

For most applications, the crosslinked hydrophobic polymer should have asufficiently high degree of crosslinking so that the composition doesnot exhibit cold flow following application to a surface, e.g. a bodysurface such as skin. As will be appreciated by those in the art, thedegree of crosslinking correlates with Mooney viscosity, a measure ofthe resistance of a raw or unvulcanized rubber to deformation asmeasured in a Mooney viscometer. A higher Mooney viscosity indicates ahigher degree of crosslinking. The Mooney viscosity of preferredhydrophobic PSAs for use herein should be at least 20 cps at 25° C., andwill generally be in the range of about 25 cps to 80 cps, preferablyabout 30 cps to 75 cps, at 25° C. The Mooney viscosities of thepreferred Kalar® series polymers herein are as follows: Kalar® 5200,40-45 cps; Kalar® 5215, 47-57 cps; Kalar® 5246, 30-40 cps; and Kalar®5275, 70-75 cps (all at 25° C.).

The molecular weight of the hydrophobic PSA is not critical, althoughthe molecular weight will typically be less than about 100,000 Da. Theamount of the polymer generally, although not necessarily, represents inthe range of about 5 wt. % to 15 wt. %, preferably about 7.5 wt. % to 12wt. %, most preferably about 7.5 wt. % to 10 wt. %, of the compositionafter drying.

Other hydrophobic polymers that may be used in place of or in additionto the hydrophobic PSA include, without limitation, hydrocarbon polymerssuch as polyethylene, acrylate polymers and copolymers, polyacrylamides,polyurethanes, plasticized ethylene-vinyl acetate copolymers,polyisobutylenes, polybutadiene, and neoprene (polychloroprene).Additional hydrophobic polymers suitable for incorporation into thehydrophobic phase are natural and synthetic elastomeric polymers,including, for example, AB, ABA, and “multiarmed” (AB)_(x) blockcopolymers, where for example, A is a polymerized segment or “block”comprising aryl-substituted vinyl monomers, preferably styrene, α-methylstyrene, vinyl toluene, and the like, B is an elastomeric, conjugatedpolybutadiene or polyisoprene block, and x has a value of 3 or more.Preferred elastomers are butadiene-based and isoprene-based polymers,particularly styrene-butadiene-styrene (SBS), styrene-butadiene (SB),styrene-isoprene-styrene (SIS), and styrene-isoprene (SI) blockcopolymers, where “S” denotes a polymerized segment or “block” ofstyrene monomers, “B” denotes a polymerized segment or block ofbutadiene monomers, and “I” denotes a polymerized segment or block ofisoprene monomers. Other suitable elastomers include radial blockcopolymers having a SEBS backbone (where “E” and “B” are, respectively,polymerized blocks of ethylene and butylene) and I and/or SI arms.Natural rubber (polyisoprene) and synthetic polyisoprene can also beused.

Commercially available hydrophobic elastomers include linear SIS and/orSI block copolymers such as Quintac® 3433 and Quintac® 3421, availablefrom Nippon Zeon Company, Ltd. (U.S. sales office—Louisville, Ky.);Vector® DPX 559, Vector® 4111 and Vector® 4113, available from Dexco, apartnership of Exxon Chemical Co. (Houston, Tex.) and Dow Chemical Co.(Midland Mich.); and Kraton® rubbers, such as Kraton 604x, KratonD-1107, Kraton D-1117, and Kraton D-1113, available from Shell ChemicalCo. (Houston, Tex.). Kraton D-1107 is a predominantly SIS elastomercontaining about 15% by weight SI blocks. Kraton D-1320x is an exampleof a commercially available (SI)_(x)I_(y) multiarmed block copolymer inwhich some of the arms are polyisoprene blocks. Commercially availablebutadiene-based elastomers include SBS and/or SB rubbers, such as KratonD-1101, D-1102 and D-1118X, from Shell Chemical Co.; Solprene® 1205, anSB block copolymer available from Housemex, Inc. (Houston, Tex.); andKraton TKG-101 (sometimes called “Tacky G”), a radial block copolymerhaving an SEBS backbone (E=ethylene block; B=butylene block) and Iand/or SI arms.

In a particularly preferred embodiment, the hydrophobic phase iscomprised of a butyl rubber, i.e., an isoprene-isobutylene copolymertypically having an isoprene content in the range of about 0.5 to 3 wt.%, crosslinked with polyisobutylene. Crosslinking may be effected usingcuring processes known to those of ordinary skill in the art and/ordescribed in the pertinent texts and literature, e.g., using radiation,chemical crosslinking, and/or heat. However, a preferred processinvolves mixing the polyisobutylene and the butyl rubber at atemperature in the range of about 80° C. to about 140° C., followed by athermal cure at a higher temperature, generally in the range of about150° C. to about 170° C., in the presence of a suitable curing agent andan organic peroxide or zinc oxide in combination with zinc stearate orstearic acid. Preferably, the reaction is carried out in the presence ofan organic peroxide. Suitable organic peroxides are generally selectedfrom: dialkyl peroxides such as t-butyl peroxide and2,2-bis(t-butylperoxy)propane; diacyl peroxides such as benzoyl peroxideand acetyl peroxide; peresters such as t-butyl perbenzoate and t-butylper-2-ethylhexanoate; perdicarbonates such as dicetyl peroxy dicarbonateand dicyclohexyl peroxy dicarbonate; ketone peroxides such ascyclohexanone peroxide and methylethylketone peroxide; andhydroperoxides such as cumene hydroperoxide and tert-butylhydroperoxide. Curing agents for this process are those compounds knownin the art as vulcanizing agents for butyl rubber, and thus include,without limitation, alkyl phenol-formaldehyde resins, dicatechol boratesalts (e.g., Permalux®, the di-ortho-tolylguanidine salt of dicatecholborate), (m-phenylene bis maleimide, 2,4,6-trimercapto-5 triazine), zincdiethyl dithiocarbamate and other dithiocarbamates, thiuram sulfides(e.g., Tetrone® A, dipentamethylene thiuram hexasulfide; and “TMTDS,”tetramethyl thiuram disulfide) preferably in combination with sulfur,alkylated phenol disulfides, and diphenyl phenylene diamine (DPPD).

Preferred curing agents for the aforementioned process are alkylphenol-formaldehyde condensation resins. Such resins may be halogenated,in which case the terminal methylol moieties of the resin arehalogenated, such that a halomethyl (e.g., a bromomethyl orchloromethyl) group is present at each terminus. These resins are idealcuring agents, insofar as the curing reaction is not accompanied byformation of any volatile organic compounds. These resins have themolecular structure

wherein n is typically an integer in the range of zero to 10 inclusive,X is hydroxyl or halo (typically bromo or chloro), R is an alkyl group,generally having 1 to 10 carbon atoms, and L is a lower alkylene orlower oxyalkylene linking group, preferably —CH₂— or —CH₂—O—CH₂—.Methylol-terminated compounds, wherein X is hydroxyl, are commerciallyavailable as, for example, TACKIROL 201 (trade name, a product of TaokaChemical Co., Ltd.) and HITANOL 2501 (trade name, a product of HitachiChemical Co., Ltd), while the dibromomethyl analog is available asSP1055 from Schenectady Chemical Company.

B. The Hydrophilic Phase

The hydrophilic phase comprises a blend of a hydrophilic polymer and acomplementary oligomer capable of crosslinking the hydrophilic polymerthrough hydrogen bonds, ionic bonds, and/or covalent bonds. Suitablehydrophilic polymers include repeating units derived from an N-vinyllactam monomer, a carboxy vinyl monomer, a vinyl ester monomer, an esterof a carboxy vinyl monomer, a vinyl amide monomer, and/or a hydroxyvinyl monomer. Such polymers include, by way of example, poly(N-vinyllactams), poly(N-vinyl acrylamides), poly(N-alkylacrylamides),substituted and unsubstituted acrylic and methacrylic acid polymers,polyvinyl alcohol (PVA), polyvinylamine, copolymers thereof andcopolymers with other types of hydrophilic monomers (e.g. vinylacetate).

Poly(N-vinyl lactams) useful herein are preferably noncrosslinkedhomopolymers or copolymers of N-vinyl lactam monomer units, with N-vinyllactam monomer units representing the majority of the total monomericunits of a poly(N-vinyl lactams) copolymer. Preferred poly(N-vinyllactams) for use in conjunction with the invention are prepared bypolymerization of one or more of the following N-vinyl lactam monomers:N-vinyl-2-pyrrolidone; N-vinyl-2-valerolactam; andN-vinyl-2-caprolactam. Nonlimiting examples of non-N-vinyl lactamcomonomers useful with N-vinyl lactam monomeric units includeN,N-dimethylacrylamide, acrylic acid, methacrylic acid,hydroxyethylmethacrylate, acrylamide, 2-acrylamido-2-methyl-1-propanesulfonic acid or its salt, and vinyl acetate.

Poly (N-alkylacrylamides) include, by way of example,poly(methacrylamide) and poly(N-isopropyl acrylamide)(PNIPAM).

Polymers of carboxy vinyl monomers are typically formed from acrylicacid, methacrylic acid, crotonic acid, isocrotonic acid, itaconic acidand anhydride, a 1,2-dicarboxylic acid such as maleic acid or fumaricacid, maleic anhydride, or mixtures thereof, with preferred hydrophilicpolymers within this class including polyacrylic acid andpolymethacrylic acid, with polyacrylic acid most preferred.

Preferred hydrophilic polymers herein are the following: poly(N-vinyllactams), particularly polyvinyl pyrrolidone (PVP) and poly(N-vinylcaprolactam) (PVCap); poly(N-vinyl acetamides), particularlypolyacetamide per se; polymers of carboxy vinyl monomers, particularlypolyacrylic acid and polymethacrylic acid; and copolymers and blendsthereof. PVP and PVCap are particularly preferred.

The molecular weight of the hydrophilic polymer is not critical;however, the number average molecular weight of the hydrophilic polymeris generally in the range of approximately 20,000 to 2,000,000, moretypically in the range of approximately 200,000 to 1,000,000.

The oligomer is “complementary” to the hydrophilic polymers in that itis capable of hydrogen bonding thereto. Preferably, the complementaryoligomer is terminated with hydroxyl groups, amino or carboxyl groups.The oligomer typically has a glass transition temperature T_(g) in therange of about −100° C. to about −30° C. and a melting temperature T_(m)lower than about 20° C. The oligomer may be also amorphous. Thedifference between the T_(g) values the hydrophilic polymer and theoligomer is preferably greater than about 50° C., more preferablygreater than about 100° C., and most preferably in the range of about150° C. to about 300° C. The hydrophilic polymer and complementaryoligomer should be compatible, i.e. capable of forming a homogeneousblend that exhibits a single T_(g), intermediate between those of theunblended components. Generally, the oligomer will have a molecularweight in the range from about 45 to about 800, preferably in the rangeof about 45 to about 600. Examples of suitable oligomers include, butare not limited to, low molecular weight polyalcohols (e.g. glycerol),oligoalkylene glycols such as ethylene glycol and propylene glycol,ether alcohols (e.g., glycol ethers), alkane diols from butane diol tooctane diol, including carboxyl-terminated and amino-terminatedderivatives of polyalkylene glycols. Polyalkylene glycols, optionallycarboxyl-terminated, are preferred herein, and polyethylene glycolhaving a molecular weight in the range of about 300 to 600 is an optimalcomplementary oligomer.

The hydrophilic polymer and the complementary oligomer should bemiscible with respect to each other and have disparate chain lengths (asmay be deduced from the above). The ratio of the weight averagemolecular weight of the hydrophilic polymer to that of the oligomershould be within about 200 and 200,000, preferably within about 1,250and 20,000. Also, the polymer and the oligomer should containcomplementary functional groups capable of hydrogen bonding, ionicallybonding, or covalently bonding to each other. Ideally, the complementaryfunctional groups of the polymer are located throughout the polymericstructure, while the functional groups of the oligomer are preferablylocated at the two termini of a linear molecule, and are not presentalong the backbone. Forming hydrogen bonds or ionic bonds between thetwo terminal functional groups of the oligomer and the correspondingfunctional groups contained along the backbone of the hydrophilicpolymer results in a noncovalently linked supramolecular network.

As discussed in co-pending application Ser. No. 09/900,697 for“Preparation of Hydrophilic Pressure Sensitive Adhesives HavingOptimized Adhesive Properties,” filed on Jul. 6, 2001 (published as U.S.patent Publication No. 2002/0037977 on Mar. 28, 2002), the ratio of thehydrophilic polymer to the complementary oligomer in the aforementionedblend affects both adhesive strength and the cohesive strength. Asexplained in the aforementioned patent application, the complementaryoligomer decreases the glass transition of the hydrophilicpolymer/complementary oligomer blend to a greater degree than predictedby the Fox equation, which is given by equation (1) $\begin{matrix}{\frac{1}{T_{g\quad{predicted}}} = {\frac{w_{pol}}{T_{g_{pol}}} + \frac{w_{pl}}{T_{g_{pl}}}}} & (1)\end{matrix}$

where T_(g predicted) is the predicted glass transition temperature ofthe hydrophilic polymer/complementary oligomer blend, w_(pol) is theweight fraction of the hydrophilic polymer in the blend, w_(pl) is theweight fraction of the complementary oligomer in the blend, T_(g pol) isthe glass transition temperature of the hydrophilic polymer, andT_(g pl) is the glass transition temperature of the complementaryoligomer. As also explained in that patent application, an adhesivecomposition having optimized adhesive and cohesive strength can beprepared from a hydrophilic polymer and a complementary oligomer byselecting the components and their relative amounts to give apredetermined deviation from T_(g predicted). Generally, to maximizeadhesion, the predetermined deviation from T_(g predicted) will be themaximum negative deviation, while to minimize adhesion, any negativedeviation from T_(g predicted) is minimized. Optimally, thecomplementary oligomer represents approximately 25 wt. % to 75 wt. %,preferably about 30 wt. % to about 60 wt. %, of the hydrophilicpolymer/complementary oligomer blend, and, correspondingly, thehydrophilic polymer represents approximately 75 wt. % to 25 wt. %,preferably about 70 wt. % to about 40 wt. %, of the hydrophilicpolymer/oligomer blend.

Another general predictor of pressure-sensitive adhesive behavior inpolymers is the ΔC_(p)T_(g) product, where ΔC_(p) is the change in heatcapacity at the polymer transition point from the glassy to theviscoelastic state. This product features a measure of the amount ofheat that has to be expended in order to provide the polymer transitionfrom the glassy to the viscoelastic state and to impart translationalmobility to polymeric segments. As the hydrophilic polymer, e.g.,polyvinyl pyrrolidone, is mixed with the complementary oligomer, e.g.,PEG-400 occurs, the ΔC_(p)T_(g) product decreases, passing through aminimum that corresponds to the maximum in adhesion. It is the productΔC_(p)T_(g) which sets the PSAs apart from non-adhesive polymers (Table1). The ΔC_(p)T_(g) values, which are associated with the adhesivePVP-PEG blends and hydrophobic PSA's (PDMS, PIB and natural rubber), arenotably grouped within a narrow area ranging from 45.0 to 92.0 J/g,predominantly near 65-80 J/g. Non-adhesive polymers exhibit higherΔC_(p)T_(g) values. TABLE 1 Glass transition characteristics ofrepresentative polymers. ΔCpTg Polymer Tg, K ΔCp, J/gK J/gPolydimethylsiloxane 150 0.30 45.0 Polyisobuthylene 200 0.40 79.6Natural rubber 200 0.46 92.0 Polyethylene 237 0.39 92.5 PEG-400 200 0.51101.4 Bisphenol polycarbonate 415 0.25 103.9 Polymethyl methacrylate 3850.29 112.8 Poly(N-vinyl pyrrolidone) 449 0.27 121.2 Polypropylene 2530.55 139.2 Polystyrene 375 0.38 141.0 Polyvinyl acetate 305 0.50 153.4Polyethylene terephthalate 340 0.49 165.7 Polyvinyl chloride 355 0.63229.9

The ΔC_(p)T_(g) value outlines a subtle balance between free volume andcohesive interactions energy in polymers (Feldstein et al. (1999), PolymMater. Sci. Eng. 81:467-468). In general, the enhanced free volume hasto be counterbalanced by a high attractive interaction energy in orderfor adhesion to appear. Enhanced free volume results in high molecularmobility and liquid-like fluidity of a PSA polymer, whereas substantialcohesive interaction energy provides cohesive toughness and rubber-likeresistance to flow.

For certain applications, particularly when high cohesive strength isdesired (such as with pressure-relieving cushions), the hydrophilicpolymer and optionally the complementary oligomer should be covalentlycrosslinked. The hydrophilic polymer may be covalently crosslinked,either intramolecularly or intermolecularly, and/or the hydrophilicpolymer and the complementary oligomer may be covalently crosslinked. Inthe former case, there are no covalent bonds linking the hydrophilicpolymer to the complementary oligomer, while in the latter case, thereare covalent crosslinks binding the hydrophilic polymer to thecomplementary oligomer. The hydrophilic polymer, or the hydrophilicpolymer and the complementary oligomer, may be covalently crosslinkedusing heat, radiation, or a chemical curing (crosslinking) agent. Thedegree of crosslinking should be sufficient to eliminate or at leastminimize cold flow under compression.

For covalently crosslinked hydrophilic polymer/complementary oligomersystems, the oligomer should be terminated at each end with a groupcapable of undergoing reaction with a functional group on thehydrophilic polymer. Such reactive groups include, for example, hydroxylgroups, amino groups, and carboxyl groups. These difunctionalizedoligomers may be obtained commercially or readily synthesized usingtechniques known to those of ordinary skill in the art and/or describedin the pertinent texts and literature.

For thermal crosslinking, a free radical polymerization initiator isused, and can be any of the known free radical-generating initiatorsconventionally used in vinyl polymerization. It has now been found thatincorporation of an acrylate-type curing agent typically used forphotochemical curing is also advantageous in the thermal crosslinking ofthe hydrophilic polymer/complementary oligomer blend. Such agentsinclude, by way of example, 1,4-butylene di-methacrylate or -acrylate;ethylene di-methacrylate or -acrylate; trimethylolpropane di- ortri-acrylate; glyceryl di-acrylate or -methacrylate; glyceryltri-acrylate or -methacrylate; glycidyl acrylate or methacrylate;pentaerythritol triacrylate or trimethacrylate; diallyl phthalate;2,2-bis(4-methacryloxyphenyl)propane; diallyl adipate;di(2-acryloxyethyl) ether; dipentaerythritol monohydroxypentaacrylate;neopentyl glycol diacrylate or dimethacrylate; polypropylene glycoldiacrylate or dimethacrylate; and1,3,5-tri-(2-methacryloxyethyl)-s-triazine; and hexamethylene diacrylateor dimethacrylate.

Preferred initiators for thermal crosslinking are organic peroxides andazo compounds, generally used in an amount from about 0.01 wt. % to 15wt. %, preferably 0.05 wt. % to 10 wt. %, more preferably from about 0.1wt. % to about 5% and most preferably from about 0.5 wt. % to about 4wt. % of the polymerizable material. Suitable organic peroxides includethose described above with respect to agents used in connection withcuring butyl rubber, i.e., dialkyl peroxides such as t-butyl peroxideand 2,2 bis(t-butylperoxy)propane, diacyl peroxides such as benzoylperoxide and acetyl peroxide, peresters such as t-butyl perbenzoate andt-butyl per-2-ethylhexanoate, perdicarbonates such as dicetyl peroxydicarbonate and dicyclohexyl peroxy dicarbonate, ketone peroxides suchas cyclohexanone peroxide and methylethylketone peroxide, andhydroperoxides such as cumene hydroperoxide and tert-butylhydroperoxide. Suitable azo compounds include azo bis (isobutyronitrile)and azo bis (2,4-dimethylvaleronitrile). The temperature for thermalcrosslinking will depend on the actual components and may be readilydeduced by one of ordinary skill in the art, but typically ranges fromabout 80° C. to about 200° C.

Crosslinking may also be accomplished with radiation, typically in thepresence of a photoinitator. The radiation may be ultraviolet, alpha,beta, gamma, electron beam, and x-ray radiation, although ultravioletradiation is preferred. Useful photosensitizers are triplet sensitizersof the “hydrogen abstraction” type, and include benzophenone andsubstituted benzophenone and acetophenones such as benzyl dimethylketal, 4-acryloxybenzophenone (ABP), 1-hydroxy-cyclohexyl phenyl ketone,2,2-diethoxyacetophenone and 2,2-dimethoxy-2-phenylacetophenone,substituted alpha-ketols such as 2-methyl-2-hydroxypropiophenone,benzoin ethers such as benzoin methyl ether and benzoin isopropyl ether,substituted benzoin ethers such as anisoin methyl ether, aromaticsulfonyl chlorides such as 2-naphthalene sulfonyl chloride, photoactiveoximes such as 1-phenyl-1,2-propanedione-2-(O-ethoxy-carbonyl)-oxime,thioxanthones including alkyl- and halogen-substituted thioxanthonessuch as 2-isopropylthioxanthone, 2-chlorothio-xanthone, 2,4 dimethylthioxanone, 2,4 dichlorothioxanone, and 2,4-diethyl thioxanone, and acylphosphine oxides. Other crosslinking agents suitable for effectingphotocuring include, without limitation, 1,4-butylene di-methacrylate or-acrylate; ethylene di-methacrylate or -acrylate; trimethylolpropane di-or tri-acrylate; glyceryl di-acrylate or -methacrylate; glyceryltri-acrylate or -methacrylate; glycidyl acrylate or methacrylate;pentaerythritol triacrylate or trimethacrylate; diallyl phthalate;2,2-bis(4-methacryloxyphenyl)-propane; diallyl adipate;di(2-acryloxyethyl) ether; dipentaerythritol monhydroxypentaacrylate;neopentyl glycol diacrylate or dimethacrylate; polypropylene glycoldiacrylate or dimethacrylate; and1,3,5-tri-(2-methacryloxyethyl)-s-triazine; hexamethylene diacrylate ordimethacrylate. Radiation having a wavelength of 200 to 800 nm,preferably, 200 to 500 nm, is preferred for use herein, and lowintensity ultraviolet light is sufficient to induce crosslinking in mostcases. However, with photosensitizers of the hydrogen abstraction type,higher intensity UV exposure may be necessary to achieve sufficientcrosslinking. Such exposure can be provided by a mercury lamp processorsuch as those available from PPG, Fusion, Xenon, and others.Crosslinking may also be induced by irradiating with gamma radiation oran electron beam. Appropriate irradiation parameters, i.e., the type anddose of radiation used to effect crosslinking, will be apparent to thoseskilled in the art.

Suitable chemical curing agents, also referred to as chemicalcross-linking “promoters,” include, without limitation, polymercaptanssuch as 2,2-dimercapto diethylether, dipentaerythritolhexa(3-mercaptopropionate), ethylene bis(3-mercaptoacetate),pentaerythritol tetra(3-mercaptopropionate), pentaerythritoltetrathioglycolate, polyethylene glycol dimercaptoacetate, polyethyleneglycol di(3-mercaptopropionate), trimethylolethanetri(3-mercaptopropionate), trimethylolethane trithioglycolate,trimethylolpropane tri(3-mercaptopropionate), trimethylolpropanetrithioglycolate, dithioethane, di- or trithiopropane and 1,6-hexanedithiol. The crosslinking promoter is added to the uncrosslinkedhydrophilic polymer to promote covalent crosslinking thereof, or to ablend of the uncrosslinked hydrophilic polymer and the complementaryoligomer, to provide crosslinking between the two components.

The hydrophilic polymer may also be crosslinked prior to admixture withthe complementary oligomer. In such a case, it may be preferred tosynthesize the polymer in crosslinked form, by admixing a monomericprecursor to the polymer with multifunctional comonomer andcopolymerizing. Examples of monomeric precursors and correspondingpolymeric products are as follows: N-vinyl amide precursors for apoly(N-vinyl amide) product; N-alkylacrylamides for apoly(N-alkylacrylamide) product; acrylic acid for a polyacrylic acidproduct; methacrylic acid for a polymethacrylic acid product;acrylonitrile for a poly(acrylonitrile) product; and N-vinyl pyrrolidone(NVP) for a poly(vinylpyrrolidone) (PVP) product. Polymerization may becarried out in bulk, in suspension, in solution, or in an emulsion.Solution polymerization is preferred, and polar organic solvents such asethyl acetate and lower alkanols (e.g., ethanol, isopropyl alcohol,etc.) are particularly preferred. For preparation of hydrophilic vinylpolymers, synthesis will typically take place via a free radicalpolymerization process in the presence of a free radical initiator asdescribed above. The multifunctional comonomer include, for example,bisacrylamide, acrylic or methacrylic esters of diols such as butanedioland hexanediol (1,6-hexane diol diacrylate is preferred), otheracrylates such as pentaerythritol tetraacrylate, and 1,2-ethylene glycoldiacrylate, and 1,12-dodecanediol diacrylate. Other usefulmultifunctional crosslinking monomers include oligomeric and polymericmultifunctional (meth)acrylates, e.g., poly(ethylene oxide) diacrylateor poly(ethylene oxide) dimethacrylate; polyvinylic crosslinking agentssuch as substituted and unsubstituted divinylbenzene; and difunctionalurethane acrylates such as EBECRYL® 270 and EBECRYL® 230 (1500 weightaverage molecular weight and 5000 weight average molecular weightacrylated urethanes, respectively—both available from UCB of Smyrna,Ga.), and combinations thereof. If a chemical crosslinking agent isemployed, the amount used will preferably be such that the weight ratioof crosslinking agent to hydrophilic polymer is in the range of about 1:100 to 1:5. To achieve a higher crosslink density, if desired, chemicalcrosslinking is combined with radiation curing.

The compositions are self-adhesive and normally do not require theaddition of tackifiers. However, tackifiers may, if desired, beincluded. Suitable tackifiers are relatively low molecular weight resins(weight average molecular weight generally less than about 50,000)having a fairly high glass transition temperature. Tackifying resinsinclude, for example, rosin derivatives, terpene resins, and syntheticor naturally derived petroleum resins. If tackifiers are incorporatedinto the present compositions, preferred tackifying resins are generallyselected from the group of non-polar tackifying resins, such asRegalrez® 1085 (a hydrogenated hydrocarbon resin) and Regalite® Resinssuch as Regalite® 1900, available from Hercules, Escorez 1304 (also ahydrocarbon resins) and Escorez® 1102 available from Exxon ChemicalCompany, Wingtac® 95 (a synthetic polyterpene resin), or Wingtack® 85,available from Goodyear Tire and Rubber. The resin representsapproximately 5 wt. % to about 15 wt. %, preferably 7.5 wt. % to 12 wt.%, and preferably 7.5 wt. % to 10 wt. %, relative to the dry adhesivecomposition.

Other components that can be advantageously incorporated into theadhesive compositions of the invention are, like the hydrophilicpolymer/complementary oligomer blend, water-absorbent materials. Suchcomponents include cellulosic polymers, e.g., cellulose esters andanalogs, with sodium carboxymethylcellulose (CMC) and hydroxypropylcellulose preferred, and with sodium CMC most preferred. Naturallyhydrophilic sorbents may also be used, e.g., collagens andglycosaminoglycans.

Incorporation of an antioxidant is optional but preferred. Theantioxidant serves to enhance the oxidative stability of thecomposition. Heat, light, impurities, and other factors can all resultin oxidation of the composition. Thus, ideally, antioxidants shouldprotect against light-induced oxidation, chemically induced oxidation,and thermally induced oxidative degradation during processing and/orstorage. Oxidative degradation, as will be appreciated by those in theart, involves generation of peroxy radicals, which in turn react withorganic materials to form hydroperoxides. Primary antioxidants areperoxy free radical scavengers, while secondary antioxidants inducedecomposition of hydroperoxides, and thus protect a material fromdegradation by hydroperoxides. Most primary antioxidants are stericallyhindered phenols, and preferred such compounds for use herein aretetrakis [methylene (3,5-di-tert-butyl-4-hydroxy-hydrocinnamate)]methane (e.g., Irganox® 1010, from Ciba-Geigy Corp., Hawthorne, N.Y.)and 1,3,5-trimethyl-2,4,6-tris[3,5-di-t-butyl-4-hydroxy-benzyl]benzene(e.g., Ethanox® 330, from Ethyl Corp.). A particularly preferredsecondary antioxidant that may replace or supplement a primaryantioxidant is tris(2,4-di-tert-butylphenyl)phosphite (e.g., Irgafos®168, Ciba-Geigy Corp.). Other antioxidants, including but not limited tomulti-functional antioxidants, are also useful herein. Multifunctionalantioxidants serve as both a primary and a secondary antioxidant.Irganox® 1520 D, manufactured by Ciba-Geigy is one example of amultifunctional antioxidant. Vitamin E antioxidants, such as that soldby Ciba-Geigy as Irganox® E17, are also useful in the present adhesivecompositions. Other suitable antioxidants include, without limitation,ascorbic acid, ascorbic palmitate, tocopherol acetate, propyl gallate,butylhydroxyanisole (BHA), butylated hydroxytoluene (BHT),bis(1,2,2,6,6-pentamethyl-4-piperidinyl)-(3,5-di-tert-butyl-4-hydroxybenzyl)butylpropanedioate,(available as Tinuvin®144 from Ciba-Geigy Corp.) or a combination ofoctadecyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate (also known asoctadecyl 3-(3′,5′-di-tert-butyl-4′-hydroxyphenyl)-propionate)(available as Naugard® 76 from Uniroyal Chemical Co., Middlebury, Conn.)and bis(1,2,2,6,6-pentamethyl-4-piperidinyl sebacate) (available asTinuvin®765 from Ciba-Geigy Corp.). Preferably, the antioxidant ispresent in amount up to about 2 wt. % of the adhesive composition;typically, the amount of antioxidant is in the range of about 0.05 wt. %to 1.5 wt. %.

However, other additives may be incorporated into the present adhesivecompositions, so long as they are not detrimental to the composition inany way. The adhesive composition may also include conventionaladditives such as fillers, chain transfer agents for controllingmolecular weight (e.g., carbon tetrabromide, mercaptans, or alcohols),preservatives, pH regulators, softeners, thickeners, pigments, dyes,refractive particles, stabilizers, toughening agents, pharmaceuticalagents, and permeation enhancers.

Absorbent fillers may be advantageously incorporated to control thedegree of hydration when the adhesive is on the skin or other bodysurface. Such fillers can include microcrystalline cellulose, talc,lactose, kaolin, mannitol, colloidal silica, alumina, zinc oxide,titanium oxide, magnesium silicate, magnesium aluminum silicate,hydrophobic starch, calcium sulfate, calcium stearate, calciumphosphate, calcium phosphate dihydrate, woven and non-woven paper andcotton materials. Other suitable fillers are inert, i.e., substantiallynon-adsorbent, and include, for example, polyethylenes, polypropylenes,polyurethane polyether amide copolymers, polyesters and polyestercopolymers, nylon and rayon. A preferred filler is colloidal silica,e.g., Cab-O-Sil® (Cabot Corporation, Boston Mass.).

Preservatives include, by way of example, p-chloro-m-cresol, phenylethylalcohol, phenoxyethyl alcohol, chlorobutanol, 4-hydroxybenzoic acidmethylester, 4-hydroxybenzoic acid propylester, benzalkonium chloride,cetylpyridinium chloride, chlorohexidine diacetate or gluconate,ethanol, and propylene glycol.

Compounds useful as pH regulators include, but are not limited to,glycerol buffers, citrate buffers, borate buffers, phosphate buffers, orcitric acid-phosphate buffers may also be included so as to ensure thatthe pH of the adhesive composition is compatible with that of anindividual's body surface.

Suitable softeners include citric acid esters, such as triethylcitrateor acetyl triethylcitrate, tartaric acid esters such as dibutyltartrate,glycerol esters such as glycerol diacetate and glycerol triacetate;phthalic acid esters, such as dibutyl phthalate and diethyl phthalate;and/or hydrophilic surfactants, preferably hydrophilic non-ionicsurfactants, such as, for example, partial fatty acid esters of sugars,polyethylene glycol fatty acid esters, polyethylene glycol fatty alcoholethers, and polyethylene glycol sorbitan-fatty acid esters.

Preferred thickeners herein are naturally occurring compounds orderivatives thereof, and include, by way of example: collagen;galactomannans; starches; starch derivatives and hydrolysates; cellulosederivatives such as methylcellulose, hydroxypropylcellulose,hydroxyethyl cellulose, and hydroxypropyl methylcellulose; colloidalsilicic acids; and sugars such as lactose, saccharose, fructose, andglucose. Synthetic thickeners such as polyvinyl alcohol,vinylpyrrolidone-vinylacetate-copolymers, polyethylene glycols, andpolypropylene glycols may also be used.

Low molecular weight plasticizers may also be incorporated into thecomposition, including, without limitation, the following: dialkylphthalates, dicycloalkyl phthalates, diaryl phthalates and mixedalkyl-aryl phthalates as represented by dimethyl phthalate, diethylphthalate, dipropyl phthalate, di(2-ethylhexyl)phthalate, di-isopropylphthalate, diamyl phthalate and dicapryl phthalate; alkyl and arylphosphates such as tributyl phosphate, trioctyl phosphate, tricresylphosphate, and triphenyl phosphate; alkyl citrate and citrate esterssuch as trimethyl citrate, triethyl citrate, tributyl citrate, acetyltriethyl citrate, and trihexyl citrate; alkyl adipates such as dioctyladipate, diethyl adipate, di(2-methylethyl)adipate, and dihexyl adipate;dialkyl tartrates such as diethyl tartrate and dibutyl tartrate; alkylsebacates such as diethyl sebacate, dipropyl sebacate and dinonylsebacate; alkyl succinates such as diethyl succinate and dibutylsuccinate; alkyl glycolates, alkyl glycerolates, glycol esters andglycerol esters such as glycerol diacetate, glycerol triacetate(triacetin), glycerol monolactate diacetate, methyl phthalyl ethylglycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate,ethylene glycol dibutyrate, triethylene glycol diacetate, triethyleneglycol dibutyrate and triethylene glycol dipropionate; and low molecularweight polyalkylene glycols (molecular weight 300 to 600) such aspolyethylene glycol 400; and mixtures thereof.

III. Adhesive Compositions Containing an Active Agent:

Any of the above-described adhesive compositions may be modified so asto contain an active agent and thereby act as an active agent deliverysystem when applied to a body surface in active agent-transmittingrelation thereto. The release of active agents “loaded” into the presentcompositions typically involves both absorption of water and desorptionof the agent via a swelling-controlled diffusion mechanism. Activeagent-containing adhesive compositions may be employed, by way ofexample, in transdermal drug delivery systems, in wound dressings, intopical pharmaceutical formulations, in implanted drug delivery systems,in oral dosage forms, and the like.

Suitable active agents that may be incorporated into the presentcompositions and delivered systemically (e.g., with a transdermal, oral,or other dosage form suitable for systemic administration of a drug)include, but are not limited to: analeptic agents; analgesic agents;anesthetic agents; antiarthritic agents; respiratory drugs, includingantiasthmatic agents; anticancer agents, including antineoplastic drugs;anticholinergics; anticonvulsants; antidepressants; antidiabetic agents;antidiarrheals; antihelminthics; antihistamines; antihyperlipidemicagents; antihypertensive agents; anti-infective agents such asantibiotics and antiviral agents; antiinflammatory agents; antimigrainepreparations; antinauseants; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics; antispasmodics; antitubercular agents;antiulcer agents; antiviral agents; anxiolytics; appetite suppressants;attention deficit disorder (ADD) and attention deficit hyperactivitydisorder (ADHD) drugs; cardiovascular preparations including calciumchannel blockers, antianginal agents, central nervous system (CNS)agents, beta-blockers and antiarrhythmic agents; central nervous systemstimulants; cough and cold preparations, including decongestants;diuretics; genetic materials; herbal remedies; hormonolytics; hypnotics;hypoglycemic agents; immunosuppressive agents; leukotriene inhibitors;mitotic inhibitors; muscle relaxants; narcotic antagonists; nicotine;nutritional agents, such as vitamins, essential amino acids and fattyacids; ophthalmic drugs such as antiglaucoma agents; parasympatholytics;peptide drugs; psychostimulants; sedatives; steroids, includingprogestogens, estrogens, corticosteroids, androgens and anabolic agents;smoking cessation agents; sympathomimetics; tranquilizers; andvasodilators including general coronary, peripheral and cerebral.Specific active agents with which the present adhesive compositions areuseful include, without limitation, anabasine, capsaicin, isosorbidedinitrate, aminostigmine, nitroglycerine, verapamil, propranolol,silabolin, foridone, clonidine, cytisine, phenazepam, nifedipine,fluacizin, and salbutamol.

For topical drug administration and/or medicated cushions (e.g.,medicated footpads), suitable active agents include, by way of example,the following:

Bacteriostatic and bactericidal agents: Suitable bacteriostatic andbactericidal agents include, by way of example: halogen compounds suchas iodine, iodopovidone complexes (i.e., complexes of PVP and iodine,also referred to as “povidine” and available under the tradenameBetadine® from Purdue Frederick), iodide salts, chloramine,chlorohexidine, and sodium hypochlorite; silver and silver-containingcompounds such as sulfadiazine, silver protein acetyltannate, silvernitrate, silver acetate, silver lactate, silver sulfate and silverchloride; organotin compounds such as tri-n-butyltin benzoate; zinc andzinc salts; oxidants, such as hydrogen peroxide and potassiumpermanganate; aryl mercury compounds, such as phenylmercury borate ormerbromin; alkyl mercury compounds, such as thiomersal; phenols, such asthymol, o-phenyl phenol, 2-benzyl-4-chlorophenol, hexachlorophen andhexylresorcinol; and organic nitrogen compounds such as8-hydroxyquinoline, chlorquinaldol, clioquinol, ethacridine, hexetidine,chlorhexedine, and ambazone.

Antibiotic agents: Suitable antibiotic agents include, but are notlimited to, antibiotics of the lincomycin family (referring to a classof antibiotic agents originally recovered from streptomyceslincolnensis), antibiotics of the tetracycline family (referring to aclass of antibiotic agents originally recovered from streptomycesaureofaciens), and sulfur-based antibiotics, i.e., sulfonamides.Exemplary antibiotics of the lincomycin family include lincomycin itself(6,8-dideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)-carbonyl]amino]-1-thio-L-threo-α-D-galactooctopyranoside),clindamycin, the 7-deoxy, 7-chloro derivative of lincomycin (i.e.,7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]-amino]-1-thio-L-threo-α-D-galacto-octopyranoside),related compounds as described, for example, in U.S. Pat. Nos.3,475,407, 3,509,127, 3,544,551 and 3,513,155, and pharmacologicallyacceptable salts and esters thereof. Exemplary antibiotics of thetetracycline family include tetracycline itself4-(dimethylamino)-1,4,4α,5,5α,6,11,12α-octahydro-3,6,12,12α-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide),chlortetracycline, oxytetracycline, tetracycline, demeclocycline,rolitetracycline, methacycline and doxycycline and theirpharmaceutically acceptable salts and esters, particularly acid additionsalts such as the hydrochloride salt. Exemplary sulfur-based antibioticsinclude, but are not limited to, the sulfonamides sulfacetamide,sulfabenzamide, sulfadiazine, sulfadoxine, sulfamerazine,sulfamethazine, sulfamethizole, sulfamethoxazole, and pharmacologicallyacceptable salts and esters thereof, e.g., sulfacetamide sodium.

Pain relieving agents: Suitable pain relieving agents are localanesthetics, including, but not limited to, acetamidoeugenol, alfadoloneacetate, alfaxalone, amucaine, amolanone, amylocaine, benoxinate,betoxycaine, biphenamine, bupivacaine, burethamine, butacaine, butaben,butanilicaine, buthalital, butoxycaine, carticaine, 2-chloroprocaine,cinchocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine,dimethisoquin, dimethocaine, diperadon, dyclonine, ecgonidine, ecgonine,ethyl aminobenzoate, ethyl chloride, etidocaine, etoxadrol, β-eucaine,euprocin, fenalcomine, fomocaine, hexobarbital, hexylcaine,hydroxydione, hydroxyprocaine, hydroxytetracaine, isobutylp-aminobenzoate, kentamine, leucinocaine mesylate, levoxadrol,lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methohexital,methyl chloride, midazolam, myrtecaine, naepaine, octacaine, orthocaine,oxethazaine, parethoxycaine, phenacaine, phencyclidine, phenol,piperocaine, piridocaine, polidocanol, pramoxine, prilocaine, procaine,propanidid, propanocaine, proparacaine, propipocaine, propofol,propoxycaine, pseudococaine, pyrrocaine, risocaine, salicyl alcohol,tetracaine, thialbarbital, thimylal, thiobutabarbital, thiopental,tolycaine, trimecaine, zolamine, and combinations thereof. Tetracaine,lidocaine and prilocaine are referred pain relieving agents herein.

Other topical agents that may be delivered using the presentcompositions as drug delivery systems include the following: antifungalagents such as undecylenic acid, tolnaftate, miconazole, griseofulvine,ketoconazole, ciclopirox, clotrimazole and chloroxylenol; keratolyticagents, such as salicylic acid, lactic acid and urea; vessicants such ascantharidin; anti-acne agents such as organic peroxides (e.g., benzoylperoxide), retinoids (e.g., retinoic acid, adapalene, and tazarotene),sulfonamides (e.g., sodium sulfacetamide), resorcinol, corticosteroids(e.g., triamcinolone), alpha-hydroxy acids (e.g., lactic acid andglycolic acid), alpha-keto acids (e.g., glyoxylic acid), andantibacterial agents specifically indicated for the treatment of acne,including azelaic acid, clindamycin, erythromycin, meclocycline,minocycline, nadifloxacin, cephalexin, doxycycline, and ofloxacin;skin-lightening and bleaching agents, such as hydroquinone, kojic acid,glycolic acid and other alpha-hydroxy acids, artocarpin, and certainorganic peroxides; agents for treating warts, including salicylic acid,imiquimod, dinitrochlorobenzene, dibutyl squaric acid, podophyllin,podophyllotoxin, cantharidin, trichloroacetic acid, bleomycin,cidofovir, adefovir, and analogs thereof; and anti-inflammatory agentssuch as corticosteroids and nonsteroidal anti-inflammatory drugs(NSAIDs), where the NSAIDS include ketoprofen, flurbiprofen, ibuprofen,naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen,oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, fenbufen, andtiaprofenic acid.

For wound dressings, suitable active agents are those useful for thetreatment of wounds, and include, but are not limited to bacteriostaticand bactericidal compounds, antibiotic agents, pain relieving agents,vasodilators, tissue-healing enhancing agents, amino acids, proteins,proteolytic enzymes, cytokines, and polypeptide growth factors. Specificsuch agents are set forth in Section IX, infra.

For topical and transdermal administration of some active agents, and inwound dressings, it may be necessary or desirable to incorporate apermeation enhancer into the composition in order to enhance the rate ofpenetration of the agent into or through the skin. Suitable enhancersinclude, for example, the following: sulfoxides such asdimethylsulfoxide (DMSO) and decylmethylsulfoxide (C₁₀MSO); ethers suchas diethylene glycol monoethyl ether (available commercially asTranscutol®) and diethylene glycol monomethyl ether; surfactants such assodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide,benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80)and lecithin (U.S. Pat. No. 4,783,450); the 1-substitutedazacycloheptan-2-ones, particularly 1-n-dodecylcyclaza-cycloheptan-2-one(available under the trademark Azone® from Nelson Research & DevelopmentCo., Irvine, Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616and 4,557,934); alcohols such as ethanol, propanol, octanol, decanol,benzyl alcohol, and the like; fatty acids such as lauric acid, oleicacid and valeric acid; fatty acid esters such as isopropyl myristate,isopropyl palmitate, methylpropionate, and ethyl oleate; polyols andesters thereof such as propylene glycol, ethylene glycol, glycerol,butanediol, polyethylene glycol, and polyethylene glycol monolaurate(PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and othernitrogenous compounds such as urea, dimethylacetamide (DMA),dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone,ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones;and organic acids, particularly salicylic acid and salicylates, citricacid and succinic acid. Mixtures of two or more enhancers may also beused.

IV. Conductive Adhesive Compositions:

The compositions of the invention can be rendered electricallyconductive for use in biomedical electrodes and other electrotherapycontexts, i.e., to attach an electrode or other electrically conductivemember to the body surface. For example, the adhesive composition may beused to attach a transcutaneous nerve stimulation electrode, anelectrosurgical return electrode, or an EKG electrode to a patient'sskin or mucosal tissue. These applications involve modification of thecomposition so as to contain a conductive species. Suitable conductivespecies are ionically conductive electrolytes, particularly those thatare normally used in the manufacture of conductive adhesives used forapplication to the skin or other body surface, and include ionizableinorganic salts, organic compounds, or combinations of both. Examples ofionically conductive electrolytes include, but are not limited to,ammonium sulfate, ammonium acetate, monoethanolamine acetate,diethanolamine acetate, sodium lactate, sodium citrate, magnesiumacetate, magnesium sulfate, sodium acetate, calcium chloride, magnesiumchloride, calcium sulfate, lithium chloride, lithium perchlorate, sodiumcitrate and potassium chloride, and redox couples such as a mixture offerric and ferrous salts such as sulfates and gluconates. Preferredsalts are potassium chloride, sodium chloride, magnesium sulfate, andmagnesium acetate, and potassium chloride is most preferred for EKGapplications. Although virtually any amount of electrolyte may bepresent in the adhesive compositions of the invention, it is preferablethat any electrolyte present be at a concentration in the range of about0.1 to about 15 wt. % of the adhesive composition. The proceduredescribed in U.S. Pat. No. 5,846,558 to Nielsen et al. for fabricatingbiomedical electrodes may be adapted for use with the adhesivecompositions of the invention, and the disclosure of that patent isincorporated by reference with respect to manufacturing details. Othersuitable fabrication procedures may be used as well, as will beappreciated by those skilled in the art.

Any absorbent additives incorporated should be compatible with allcomponents of the hydrogel-containing cushion, and should also serve toreduce or eliminate cold flow under compression. Suitable absorbentadditives include, by way of example, polyacrylate starch derivatives,starches, starch copolymers, and the like.

V. Fabrication Processes:

The compositions of the invention are generally prepared by separatelyincorporating the necessary curing agents into each phase, and thenblending the phases. That is, the curing agent for the hydrophobicphase, along with any catalysts or co-curing agents, are loaded into thecomposition that will serve as the hydrophobic phase, and, ifapplicable, the curing agent for the hydrophilic phase is loaded intothe composition that will serve as the hydrophilic phase. At this point,the hydrophobic and hydrophilic compositions are mixed and curing isconducted using the appropriate means, e.g., radiation or heat.

VI. Wound Dressings:

In a further embodiment, the compositions of the invention are asabsorbent materials in a wound dressing. The composition may beformulated so as to contain a pharmacologically active agent. Preferredactive agents, in this embodiment, include the bacteriostatic andbactericidal agents, antibiotic agents, and pain-relieving agents setforth in Section IV, as well as the following:

Topical Vasodilators: Such compounds are useful for increasing bloodflow in the dermis, and preferred topical vasodilators are those knownas rubefacients or counterirritants. Rubefacient agents includenicotinic acid, nicotinates such as methyl, ethyl, butoxyethyl,phenethyl and thurfyl nicotinate, as well as the essential oils such asmustard, turpentine, cajuput and capsicum oil, and components thereof.Particular preferred such compounds include, but are not limited to,methyl nicotinate, nicotinic acid, nonivamide, and capsaicin.

Proteolytic enzymes: Proteolytic enzymes herein are those that areeffective wound cleansing agents, and include, for example, pepsin,trypsin, collagenase, chymotrypsin, elastase, carboxypeptidase,aminopeptidase, and the like.

Peptide, proteins, and amino acids: Suitable peptides and proteins aretissue-healing enhancing agents (also referred to in the art as “tissueregenerative agents”) such as collagen, glycosaminoglycans (e.g.,hyaluronic acid, heparin, heparin sulfate, chondroitin sulfate, etc.),proteoglycans (e.g., versican, biglycan) substrate adhesion molecules(e.g., fibronectin, vitronectin, laminin), polypeptide growth factors(e.g., platelet-derived growth factor, a fibroblast growth factor, atransforming growth factor, an insulin-like growth factor, etc.), andother peptides such as fibronectin, vitronectin, osteopontin, andthrombospondin, all of which contain the tripeptide sequence RGD(arginine-glycine-aspartic acid), a sequence generally associated withadhesive proteins and necessary for interaction with cell surfacereceptors.

One embodiment of a wound dressing of the invention is represented inFIG. 1. The wound dressing is generally indicated at 10, and comprises:an outer backing layer 12 that serves as the external surface of thedressing following application to the body surface; a skin contactadhesive layer 14 laminated thereto, which may or may not be an adhesivecomposition of the invention, optionally containing one or morepharmacologically active agents; an absorbent wound-contacting region 16comprised of an adhesive composition of the invention and located on theon the wound contacting side of layer 14; and a removable release liner18. Upon removable of the release liner, the dressing is applied to abody surface in the region of a wound, and placed on the body surface sothat the wound-contacting region 16 is directly over the wound. In thisembodiment, the wound dressing adheres to the skin surrounding the woundas a result of the exposed skin contact adhesive areas 20 and 22surrounding the wound-contacting region. If the wound-contactingcomposition is prepared so that it has some degree of tack prior toabsorption of water (as in, e.g., wound exudate), the dressing adheresin the central region as well. It should be noted that any of theadhesive compositions of the invention may be used as a wound dressingherein, providing that, as noted above, the adhesive composition issubstantially nontacky or at most slightly tacky. Also, those adhesivecompositions that exhibit a high degree of absorbency are preferred. Theother components of the wound dressing of FIG. 1 are as follows:

The backing layer 12 of the wound dressing functions as the primarystructural element and provides the dressing with flexibility. Thematerial used for the backing layer should be inert and incapable ofabsorbing drug, enhancer or other components of the wound-contactingadhesive composition. Also, the material used for the backing layershould permit the device to follow the contours of the skin and be worncomfortably on areas of skin such as at joints or other points offlexure, that are normally subjected to mechanical strain with little orno likelihood of the device disengaging from the skin due to differencesin the flexibility or resiliency of the skin and the device. Examples ofmaterials useful for the backing layer are polyesters, polyethylene,polypropylene, polyurethanes and polyether amides. The layer ispreferably in the range of about 15 microns to about 250 microns inthickness, and may, if desired, be pigmented, metallized, or providedwith a matte finish suitable for writing. The layer is preferablyalthough not necessarily nonocclusive (or “breathable”), i.e., ispreferably permeable to moisture.

The skin contact adhesive layer 14 may be composed of a conventionalpressure-sensitive adhesive such as may be selected from polysiloxanes,polyisobutylenes, polyacrylates, polyurethanes, polyisobutylene, and thelike. Alternatively, the layer may be made from an adhesive compositionof the invention, as described in Sections II, III and IV, supra.

Release liner 18 is a disposable element that serves to protect thedevice prior to application. The release liner should be formed from amaterial impermeable to the drug, vehicle and adhesive, and that iseasily stripped from the contact adhesive. Release liners are typicallytreated with silicone or fluorocarbons, and are commonly made frompolyesters and polyethylene terephthalate.

In another embodiment, illustrated in FIG. 2, the backing layer 24 ofthe wound dressing shown is composed of a tacky or at least slightlytacky adhesive composition of the invention, but is provided with anontacky upper surface 26. The wound-contacting hydrogel material 28 isadhered to the skin-contacting side of the backing layer 24. Uponremoval of release liner 30, the wound dressing is applied to anindividual's skin in the region of a wound so that the wound-contactinghydrogel material is placed directly over the wound. As with theembodiment of FIG. 1, the wound dressing adheres to the body surface byvirtue of the exposed regions 32 and 34 of the adhesive composition. Inthis case, it is preferred that both the backing layer and the adhesivecomposition be translucent, so that the extent of wound healing can beviewed directly through the backing, eliminating the need for frequentreplacement or removal of the wound dressing.

In a further embodiment, illustrated in FIG. 3, the perimeter 36 of thewound dressing is made of a different material than the interior region38 of the backing. In this case, the perimeter 36 is comprised of a skincontact adhesive that may or may not be an adhesive composition of theinvention, although the upper, outwardly facing surface 40 of theperimeter is nontacky. The interior region 38 of the backing ispreferably comprised of an adhesive composition of the invention. Theskin-facing side of the interior region 38 may or may not be tacky,although the upper surface 42 of the interior region 38 should benontacky. The wound-contacting hydrogel material 44 is adhered to theunderside (i.e., the skin contacting side) of the backing and iscentrally located within interior region 38. As with the embodiment ofFIG. 2, it is preferred that both the interior region 38 of the backingand the wound-contacting hydrogel material 44 are translucent.Generally, the perimeter adhesive will be opaque. The removable releaseliner is indicated at 46. In a variation on the embodiment of FIG. 3, anouter layer may be laminated to the upper surface of the device shown.Such an outer layer would then serve as the actual backing, with thelayer represented by interior region 38 and perimeter 36 representing anintermediate layer.

FIG. 4 is a bottom plan view of the wound dressing of FIG. 3 (with therelease liner having been removed), taken along lines 4-4; the viewshown is thus the skin-contacting face of the dressing. As describedwith respect to FIG. 3, the wound-contacting hydrogel material 44 islocated within the interior region 38 of the backing, and the perimeteradhesive 36 surrounds that region.

In still another embodiment, illustrated in FIG. 5, the wound dressingcontains three layers, a backing layer 48, a central adhesive layer 50typically composed of a conventional pressure-sensitive adhesive, and awound-contacting hydrogel layer 52, wherein the three layers arecoextensive such that there is no distinct perimeter region as there isin the embodiments of FIG. 1 to 4. During storage and prior to use, theskin contacting side 54 of the dressing is protected with a releaseliner (not shown), as above.

FIG. 6 illustrates a variation of the embodiment of FIG. 5, wherein thewound dressing is composed of only two layers, a backing 56 and awound-contacting hydrogel layer 58 laminated thereto and coextensivetherewith. In this case, the hydrogel layer 58 must have sufficient tackso as to adhere to the backing layer, even after water absorption. Aswith the embodiments discussed above, the skin contacting side 60 isprotected with a release liner (not shown) during storage and prior touse.

VII. Active Agent Delivery Systems:

An active agent may be delivered to a body surface by simply placing acomposition of the invention on a body surface in activeagent-transmitting relation thereto. Alternatively, an activeagent-containing composition may be incorporated into a delivery systemor “patch.” In manufacturing such systems, the hydrogel adhesivecomposition may be cast or extruded onto a backing layer or releaseliner and will serve as the skin-contacting face of the system and actas an active agent reservoir. Alternatively, the adhesive compositionmay be used as an active agent reservoir within the interior of such asystem, with a conventional skin contact adhesive laminated thereto toaffix the system to a patient's body surface.

Systems for the topical, transdermal or transmucosal administration ofan active agent may comprise: (A) a reservoir containing atherapeutically effective amount of an active agent; (B) an adhesivemeans for maintaining the system in active agent transmittingrelationship to a body surface; and (C) a backing layer as described inthe preceding section, wherein (D) a disposable release liner covers theotherwise exposed adhesive, protecting the adhesive surface duringstorage and prior to use (also as described in the preceding section).In many such devices, the reservoir can also serve as the adhesivemeans, and the adhesive compositions of the invention can be used as thereservoir and/or the adhesive means.

Any number of active agents can be administered using such deliverysystems. Suitable active agents include the broad classes of compoundsnormally delivered to and/or through body surfaces and membranes; suchactive agents are described in Section V. With some active agents, itmay be necessary to administer the agent along with a permeationenhancer in order to achieve a therapeutically effective flux throughthe skin. Suitable enhancers are also described in Section IV.

Accordingly, an active agent-containing composition is incorporated intothe reservoir, either during manufacture of the system or thereafter.The composition will contain a quantity of an active agent effective toprovide the desired dosage over a predetermined delivery period. Thecomposition will also contain a carrier (e.g., a vehicle to solubilizethe active agent), a permeation enhancer, if necessary, and optionalexcipients such as colorants, thickening agents, stabilizers,surfactants and the like. Other agents may also be added, such asantimicrobial agents, to prevent spoilage upon storage, i.e., to inhibitgrowth of microbes such as yeasts and molds. Suitable antimicrobialagents are typically selected from the group consisting of the methyland propyl esters of p-hydroxybenzoic acid (i.e., methyl and propylparaben), sodium benzoate, sorbic acid, imidurea, and combinationsthereof.

Preferably, the delivery system is “monolithic,” meaning that a singlelayer serves as both the active agent-containing reservoir and the skincontact adhesive. However, the reservoir and the skin contact adhesivemay be separate and distinct layers. Also, more than one reservoir maybe present, each containing a different component for delivery into theskin. The present adhesive compositions may be used as any or all of theaforementioned layers.

The backing layer of the drug delivery system functions as the primarystructural element of the transdermal system, and preferred backingmaterials in transdermal drug delivery devices are the same as thosedescribed in the preceding section with respect to wound dressings.

Additional layers, e.g., intermediate fabric layers and/orrate-controlling membranes, may also be present in a transdermal drugdelivery system. Fabric layers may be used to facilitate fabrication ofthe device, while a rate-controlling membrane may be used to control therate at which a component permeates out of the device. The component maybe a drug, a permeation enhancer, or some other component contained inthe drug delivery system.

In any of these systems, it may be desirable to include arate-controlling membrane in the system on the body surface side of thedrug reservoir. The materials used to form such a membrane are selectedto limit the flux of one or more components contained in the drugformulation, and the membrane may be either microporous or dense.Representative materials useful for forming rate-controlling membranesinclude polyolefins such as polyethylene and polypropylene, polyamides,polyesters, ethylene-ethacrylate copolymer, ethylene-vinyl acetatecopolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinylethylacetate copolymer, ethylene-vinyl propylacetate copolymer,polyisoprene, polyacrylonitrile, ethylene-propylene copolymer,polysiloxane-polycarbonate block copolymer and the like.

The compositions of the invention may also serve to deliver an activeagent using other routes of administration. For example, thecompositions may be formulated with excipients, carriers and the likesuitable for oral administration of an orally active drug. Thecompositions may also be used in buccal and sublingual drug delivery,insofar as the compositions can adhere well to moist surfaces within themouth. In buccal and sublingual systems, hydrolyzable and/or bioerodiblepolymers may be incorporated into the compositions to facilitate gradualerosion throughout a drug delivery period. Still other types offormulations and drug delivery platforms may be prepared using thepresent compositions, including implants, rectally administrablecompositions, vaginally administrable compositions, and the like.

IX. Cushions and Other Products Requiring Adhesion to a Body Surface:

The adhesive compositions of the invention are useful in any number ofadditional contexts wherein adhesion of a product to a body surface iscalled for or desirable. These applications include, for example,pressure-relieving cushions for application to a foot, wherein thecushions may or may not contain medication for transdermal or topicaldelivery, e.g., in the treatment of dicubitis, veinous and diabetic footulcers, or the like. Suitable active agents are described in Section IV.

Such cushions will generally be comprised of a flexible, resilient outerlayer, fabricated from a foam pad or fabric, with a layer of an adhesivecomposition of the invention laminated thereto for application to theskin surface. Suitable cushions include heel cushions, elbow pads, kneepads, shin pads, forearm pads, wrist pads, finger pads, corn pads,callus pads, blister pads, bunion pads and toe pads.

The compositions of the invention are also useful in a host of othercontexts, e.g., as adhesives for affixing medical devices, diagnosticsystems and other devices to be affixed to a body surface, and in anyother application wherein adhesion to a body surface is necessary ordesired. The adhesive compositions are also useful as sealants forostomy devices, prostheses, and face masks, as sound, vibration orimpact absorbing materials, as carriers in cosmetic and cosmeceuticalgel products, and will have other uses known to or ascertainable bythose of ordinary skill in the art, or as yet undiscovered.

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of polymer chemistry, adhesivemanufacture, and hydrogel preparation, which are within the skill of theart. Such techniques are fully explained in the literature.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, theforegoing description, as well as the examples that follow, are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications will be apparent to those skilled in theart to which the invention pertains. All patents, patent applications,journal articles and other references cited herein are incorporated byreference in their entireties.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the compounds of the invention, and are not intended tolimit the scope of what the inventors regard as their invention. Effortshave been made to ensure accuracy with respect to numbers (e.g.,amounts, temperatures, etc.) but some errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in degrees Celsius (° C.), and pressure is at or nearatmospheric.

The following abbreviations and tradenames are used in the examples:

-   -   Br-APFR (SP-1055): dibromo-terminated alkyl phenolformaldehyde        resin (Schenectady)    -   APFR: alkyl phenolformaldehyde resin (identical to SP-1055 but        containing terminol methylol groups) (obtained from M.V.        Lomonosov Moscow State Academy of Fine Chemical Technology)    -   BPO: benzoyl peroxide    -   BR: butyl rubber, 2 wt. % isoprene content    -   HPC: hydroxypropyl cellulose    -   PIB: polyisobutylene    -   RH: relative humidity    -   SR 399: dipentaerythritol monohydroxypentaacrylate (Sartomer)

EXAMPLE 1

The following example describe formulation of a pressure-sensitiveadhesive composition based on a cured blend of polyisobutylene withbutyl rubber with PVP-PEG water sorbents, and optionally withcellulose-based water sorbents, to form a two-phase adhesive matrix.

Mixing procedures for the adhesive blend: Two methods of mixing wereused: a laboratory mixer of rotor-plunger type (I) and a Haake mixersupplied with a sigma-blade and Banbary rotors (II). With the lattermethod, a sample is loaded into a working chamber and heated to thedesired temperature, at which point a rotating agitator was introducedto a predetermined depth to mix the composition. This procedure wasrepeated several times to obtain a homogeneous mixture. Thetemperature-time regime of mixing depended on the components used,particularly on the curing agent used. Usually, mixing may be carriedout at a temperature >100° C. However, if Br-APFR was used as the curingagent, the temperature was decreased to 60° C. and the curing agent thenadded to the PIB-BR blend. The temperature profile was similar when aHaake mixer was used. The homogeneity of mixing was established byachieving of a stable level of a torque and confirmed microscopically byanalyzing a pressed adhesive film.

Pressing and curing adhesive films: The prepared adhesive blends werepressed between two release liners at an applied pressure in the rangeof I to 3 MPa. The formulations loaded with APFR curing agent werehot-pressed at 120° C., whereas the formulations loaded with SP1055curing agent and mixed in the Haake were pressed at room temperature.The adhesive films loaded with APFR were then cured by annealing in anoven at 160° C. for one hour. The adhesive films loaded with SP1055 werecured at 120° C. for 30 minutes.

Patch preparation: The cured adhesive films were laminated to PU backingfilm with subsequent die cutting of the patches. The thickness of theadhesive layer in the obtained patches varied from 350 to 700 μm. Toprovide a gradual decrease of adhesive layer thickness toward patchedges, pressing molds were designed and constructed with the thicknessof central part ˜500-700 μm and peripheral part of 100-200 μm.

Preparation of the hydrophobic phase: The hydrophobic phase was preparedby blending PIB with BR. Although neither PIB nor BR is a good adhesive,mixing the two results in enhancement of adhesive properties within awide concentration range, as indicated in FIG. 7. That figure gives thepeel strength data obtained for a PIB/BR blends at a range of PIB:BRratios. As the maximum peel strength was observed with a blendcontaining 40% of PIB and 60% BR, that composition was used as a basisfor preparation of an adhesive composition according to the invention.In FIG. 7, Curve A was produced by tenfold PIB-BR film pressing at acompression stress of 1-2 MPa and a temperature of 120° C., while CurveB was produced by mixing with a high speed mixer at a temperature of170° C. for 20 minutes prior to curing the adhesive film. To obtaincohesive strength (e.g., for cushions and other pressure-relieving orweight-bearing applications), the PIB-BR blend should be cured. SincePIB contains no double bonds and cannot be crosslinked, curing g thePIB-BR blends is made possible via BR crosslinking.

EXAMPLE 2

Curing a PVP-PEG hydrogel dispersed within the hydrophobic polymer:

Cured PVP-PEG hydrogels were found to be highly hygroscopic. Atrelatively low degrees of hydration, these hydrogels provide adhesiveand viscoelastic properties that allow them to be used for SCA matricesin cushion patches. If, however, such hydrogels absorb more than about15% water, they swell so much that they become unsuitable for cushionusage. In order to decrease the PVP-PEG hydrogel hygroscopicity, it wasfound useful to mix the hydrogel with an appropriate hydrophobicadhesive. The following experimental work was carried out to determineconditions under which such mixtures can be cured so that they becomeviscoelastic at room temperature and have adhesive properties suitablefor use in cushion pads. In these experiments, a PVP-PEG hydrogel wasmixed with a PIB-BR-Regalite adhesive. UV-curing to produce PVP-PEGcrosslinking, employing dipentaerythritol monohydroxy pentaacrylate SR399 (Sartomer) as curing agent and benzoyl peroxide (BPO) as aninitiator of radical polymerization, was implemented at elevatedtemperatures. The results of these experiments are shown in FIG. 8. InFIG. 8, the indivudal curves are as follows—1: SR/PVP weight ratio is 5,T=100° C. 2: SR/PVP=5, 90° C. 3: SR/PVP=2, 105° C. 4: SR/PVP=2, 95° C.As can be seen in this figure, crosslinking was found to start at about80° C. At relatively high SR 399 loading, the curing took about 15 min,both at 90 and 100° C. At lower curing agent concentrations, thecrosslinking took longer, whereas an increase in temperature acceleratedthe curing significantly. The maximum achieved level of shear stress,which relates to the blend viscosity and crosslinking density, was foundto be nearly independent of the SR 399/PVP ratio.

Next, experiments were performed in which the PVP-PEG hydrogel, with orwithout curing agent SR 399, was mixed with PIB-BR-Regalite hydrophobicadhesive, with or without APFR as a curing (crosslinking) agent. Themixtures were cured at 160° C. As shown in FIG. 9, curing only occurredif both phases (hydrophobic and hydrophilic) contained their relevantcrosslinkers. In FIG. 9, the first [+] or [−] sign refers to thepresence or absence of curing agent in the hydrophobic phase, while thesecond [+] or [−] sign refers to the presence or absence of curing agentin the hydrophilic phase. In order for the mixture to cure and blendproperly, each phase (hydrophobic and hydrophilic) had to be loaded withits relevant crosslinker prior to mixing.

EXAMPLE 3

Adhesive properties of PIB-BR blends with hydrophilic sorbents:

As shown in FIG. 10, mixing of a hydrophobic adhesive with 40% or moreof a nonadhesive hydrophilic sorbent resulted in a gradual decrease ofadhesion. If, however, the hydrophilic phase was the adhesive PVP-PEGhydrogel, the blending was not accompanied by a loss of adhesion. Thistrend was found to be typical of any hydrophobic adhesive andhydrophilic sorbent.

EXAMPLE 4

Effects of blending with hydrophilic sorbents on the viscoelasticbehavior of hydrophobic adhesives:

To determine the viscoelastic properties of various two-phase adhesives,retardation analysis was employed, based on Equation 2: $\begin{matrix}{{J(t)} = {{t_{1}/\eta_{o}} + {\sum\limits_{1}^{i}{J_{i} \cdot {\mathbb{e}}^{{\lbrack{- {({t - t_{1}})}}\rbrack}/\lambda_{i}}}}}} & (2)\end{matrix}$In this equation, the recovery response of a viscoelastic sample can bedescribed in terms of the compliance J(t), which is expressed as afunction of retardation times λi, where i=1, 2, 3 etc., η₀ is aninstantaneous dynamic viscosity (the material constant characterizingthe resistance of a liquid against being forced to flow), and t_(i) is ameasurement time. For infinite time (t) all e-functions become zero andthus the equation reduces to J(t=∞)=t_(i)/η₀, which equals the permanentstrain, i.e. the amount of viscous squeezing flow of the sample. Fort₁=0 and J_(2,3 . . .) =0 the function (2) matches the Kelvin-Voigtmodel. The retardation analysis was performed using the Microcal Originsoftware with a three-term model J_(eq)(t)=J₀+J₁+J₂, where J_(eq)(t) isthe equilibrium retardation compliance (reciprocal of equilibriumretardation modulus).

The results, presented in Table 2, are in a close agreement with thoseobtained using the Kelvin-Voigt model. The present data are highlyinformative regarding the relaxation properties of the variouscomponents of the adhesive materials. TABLE 2 Results of retardationanalysis of several two-phase adhesives using Equation 2 SqueezingComposition force, N J₀, Pa⁻¹ J₁ J₂ J_(eq) G_(eq), Pa λ₁, sec λ₂ PIB-BR(1:1) + 0.5 5.94 10⁻⁶ 1.68 10⁵ 100 5% APFR, 1 3.14 10⁻⁶ 3.19 10⁵ 106uncured 5 6.27 10⁻⁷ 1.6 10⁶ 106 PIB-BR (1:1) + 0.5 8.3 10⁻⁶ 9 10⁻⁶ 1.731⁻⁵ 5.78 10⁴ 2.7 10⁻¹⁰ 213 5% APFR, 1 6.58 10⁻⁶ 3.43 10⁻⁶ 1 10⁻⁵ 1.10⁵ 110⁻⁶ 812 cured 5 4.7 10⁻⁶ 1 10⁻⁵ 1.47 10⁻⁵ 6.8 10⁴ 268 1185 PIB 70% +0.5 8.53 10⁻⁷ 1.17 10⁶  45 HPC 30% 1 4.67 10⁻⁷ 2.14 10⁶  45 5 3.17 10⁻⁶3.15 10  33 PIB − BR 0.5 1.3 10⁻¹² 7.65 10⁻⁷ 1.32 10⁻⁶ 2 10⁻⁶ 5 10⁵ 0.0001 124 (40:60) + 1 1.8 10⁻²⁴ 3.87 10⁻⁷ 1.2 10⁻⁶ 1.6 10⁻⁶ 6.25 10⁻⁵ 11.27 250 30% − HPC 5 1.9 10⁻⁹ 4.4 10⁻⁷ 3.5 10⁻⁷ 7.9 10⁻⁷ 1.26 10⁶  30540 50% (PIB 0.5 4.61 10⁻⁸ 5.96 10⁻⁶ 5.38 10⁻⁶ 1.13 10⁻⁶ 8.82 10⁴  42611 30% + BR 1 0 2.9 10⁻⁶ 3.6 10⁻⁶ 6.5 10⁻⁶ 1.5 10⁵ 160 955 40% +Regalite 5 0 4.43 10⁻⁷ 2.26 10⁶ 564 30%) + 50% PVP-PEG (64/36)

The low J₀ values found for the cured systems, and the blends containingHPC, are a sign of negligible flow contribution. It is important to notethat HPC has been found to depress dramatically the squeezing flow ofPIB and PIB-BR mixtures, whereas it has a weaker effect on otheradhesives, e.g., DuraTak adhesives.

1. A method for preparing a two-phase, water-absorbent bioadhesivecomposition comprising: (a) preparing a crosslinkable hydrophobiccomposition comprised of a hydrophobic polymer and at least one agenteffective to crosslink the polymer; and (b) preparing a hydrophiliccomposition comprised of a hydrophilic polymer and a complementaryoligomer capable of crosslinking the hydrophilic polymer throughhydrogen bonding, ionic bonding, and/or covalent bonding; (c) admixingthe crosslinkable hydrophobic composition with the hydrophiliccomposition; and (d) crosslinking the hydrophobic polymer in theadmixture.
 2. The method of claim 1, wherein the complementary oligomeris effective to crosslink the hydrophilic polymer in the presence of acuring agent.
 3. The method of claim 2, wherein (d) further includescrosslinking the hydrophilic polymer.
 4. The method of claim 3, wherein(d) is carried out at a temperature effective to thermally crosslinkboth the hydrophobic polymer and the hydrophilic polymer.
 5. The methodof claim 4, wherein the hydrophobic polymer is butyl rubber and the atleast one agent comprises polyisobutylene.
 6. The method of claim 5,wherein the at least one agent additionally comprises an organicperoxide.
 7. The method of claim 4, wherein the curing agent ispentaerythritol monohydroxypentaacrylate.